The quality of life for millions of Americans is adversely affected by salivary gland dysfunction. A variety of etiologies contribute to the existence of dry mouth, including the use of xenogenic medications, Sjogren's syndrome, radiation therapy, or systemic diseases such as diabetes mellitus. The development of interventions to improve function for these individuals requires a thorough understanding of the molecular physiology of salivary glands. The current fluid secretion model predicts that saliva is produced as a two step process whereby acinar cells initially secrete an isotonic plasma-like fluid, which is subsequently modified by ductal cells to conserve NaCl. Chloride (Cl) channels and chloride/bicarbonate (Cl/HCO3) exchangers are key transport mechanisms involved in transepithelial Cl movement, the driving force for both the secretion of fluid and the resorption of NaCl. At least four distinct types of Cl channels and three different anion exchangers have been detected in salivary gland cells. Although the general biophysical properties of these different classes of proteins are known, major gaps exist in our knowledge of their regulation and the contribution each makes to the overall secretion process. Thus, to verify and refine our understanding of the function of these proteins in salivary gland cells, Aim 1 will examine the regulation of these proteins by secretagogues. It is hypothesized that those Cl channels and Cl/HCO3 exchangers necessary for secretion will be activated during stimulation. Aim 2 will test the hypothesis that the localization and expression of each protein is consistent with its predicted function. The cell type in which each transcript is expressed and the distribution of each protein in the plasma membrane should reflect the role that the transporter plays in fluid secretion. Aim 3 will directly test hypotheses as to which Cl transport proteins are essential to the fluid secretion process through the study of animals lacking functional expression of a specific gene. This multidisciplinary approach will define the essential Cl transport mechanisms involved in the production of saliva, critical information in the development of treatments for salivary gland dysfunction. Furthermore, the results of these studies will provide a foundation for future studies to analyze the in vivo structure/function relationship of a given Cl transporter.